Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens.

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.

Peer support to assist in transition to adult services.

A peer support worker employment initiative was developed to help young service users with the transition from child and adolescent to adult mental health services, an area that needs improving nationally. This article describes how the initiative was set up and its effectiveness.

Food insecurity in adults with severe mental illness living in Northern England: A co-produced cross-sectional study.

AIM: This study aimed to explore food insecurity prevalence and experiences of adults with severe mental illness living in Northern England. METHODS: This mixed-methods cross-sectional study took place between March and October 2022. Participants were adults with self-reported severe mental illness living in Northern England. The survey included demographic, health, and financial questions. Food insecurity was measured using the US Department of Agriculture Adult Food Security measure. Quantitative data were analysed using descriptive statistics and binary logistic regression; and qualitative data using content analysis. RESULTS: In total, 135 participants completed the survey, with a mean age of 44.7 years (SD: 14.1, range: 18-75 years). Participants were predominantly male (53.3%), white (88%) and from Yorkshire (50.4%). The food insecurity prevalence was 50.4% (n = 68). There was statistical significance in food insecurity status by region (p = 0.001); impacts of severe mental illness on activities of daily living (p = 0.02); and the Covid pandemic on food access (p < 0.001). The North West had the highest prevalence of food insecurity (73.3%); followed by the Humber and North East regions (66.7%); and Yorkshire (33.8%). In multivariable binary logistic regression, severe mental illness' impact on daily living was the only predictive variable for food insecurity (odds ratio = 4.618, 95% confidence interval: 1.071-19.924, p = 0.04). CONCLUSION: The prevalence of food insecurity in this study is higher than is reported in similar studies (41%). Mental health practitioners should routinely assess and monitor food insecurity in people living with severe mental illness. Further research should focus on food insecurity interventions in this population.

A candidate antibody drug for prevention of malaria.

Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO's preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.

Effects of interventions on depression and anxiety in older people with physical health problems in the criminal justice system: a systematic review.

The demand for health care in older people involved in the criminal justice system is high. The prevalence of mental and physical health conditions for people living in prison is greater than in community populations. After systematically searching 21 databases, we found no targeted interventions to support depression or anxiety for this group of people. 24 studies (including interventions of yoga, creative-arts-based programmes, positive psychology, or mindfulness-based interventions and psychotherapy) did contain people older than 50 years, but this only represented a minority (10%) of the overall study population. No single study reported outcomes of physical health. Future interventions need to consider the needs and views of this vulnerable group. Specific gendered and coproduced interventions are required to enhance the implementation, feasibility, and acceptability of interventions that are delivered in prisons.

Iron catalyzed asymmetric oxyamination of olefins.

The regioselective and enantioselective oxyamination of alkenes with N-sulfonyl oxaziridines is catalyzed by a novel iron(II) bis(oxazoline) complex. This process affords oxazolidine products that can be easily manipulated to yield highly enantioenriched free amino alcohols. The regioselectivity of this process is complementary to that obtained from the analogous copper(II)-catalyzed reaction. Thus, both regioisomers of enantioenriched 1,2-aminoalcohols can be obtained using oxaziridine-mediated oxyamination reactions, and the overall sense of regiochemistry can be controlled using the appropriate choice of inexpensive first-row transition metal catalyst.

Experiences of a community of research practice: a service evaluation.

BACKGROUND: A community of research practice (CRP) was established to increase research capacity and provide learning opportunities and networking for healthcare practitioners, working within a Children's Care Group. The CRP aimed to engage research-interested practitioners in research to develop their skills and confidence, encourage networking, and build research capacity. AIM: To report the results of a service evaluation that was undertaken to review the CRP's value in practice. DISCUSSION: Thematic analysis revealed four themes - 'positive environment', 'confidence', 'professional development' and 'networking' - highlighting benefits from the CRP, alongside the challenges encountered. CONCLUSION: This article highlights the significant contribution of CRP for practitioners in the context of an innovative organisation with a supportive culture. IMPLICATIONS FOR PRACTICE: A CRP empowers healthcare practitioners to engage with research while in clinical practice, enabling increased research confidence, and the development of research skill and knowledge and enhanced networking. CRP can potentially influence recruitment and retention.

A nonfunctional copy of the salmonid sex-determining gene (sdY) is responsible for the "apparent" XY females in Chinook salmon, Oncorhynchus tshawytscha.

Many salmonids have a male heterogametic (XX/XY) sex determination system, and they are supposed to have a conserved master sex-determining gene (sdY) that interacts at the protein level with Foxl2 leading to the blockage of the synergistic induction of Foxl2 and Nr5a1 of the cyp19a1a promoter. However, this hypothesis of a conserved master sex-determining role of sdY in salmonids is challenged by a few exceptions, one of them being the presence of naturally occurring "apparent" XY Chinook salmon, Oncorhynchus tshawytscha, females. Here, we show that some XY Chinook salmon females have a sdY gene (sdY-N183), with 1 missense mutation leading to a substitution of a conserved isoleucine to an asparagine (I183N). In contrast, Chinook salmon males have both a nonmutated sdY-I183 gene and the missense mutation sdY-N183 gene. The 3-dimensional model of SdY-I183N predicts that the I183N hydrophobic to hydrophilic amino acid change leads to a modification in the SdY ß-sandwich structure. Using in vitro cell transfection assays, we found that SdY-I183N, like the wild-type SdY, is preferentially localized in the cytoplasm. However, compared to wild-type SdY, SdY-I183N is more prone to degradation, its nuclear translocation by Foxl2 is reduced, and SdY-I183N is unable to significantly repress the synergistic Foxl2/Nr5a1 induction of the cyp19a1a promoter. Altogether, our results suggest that the sdY-N183 gene of XY Chinook females is nonfunctional and that SdY-I183N is no longer able to promote testicular differentiation by impairing the synthesis of estrogens in the early differentiating gonads of wild Chinook salmon XY females.

Convergent antibody evolution and clonotype expansion following influenza virus vaccination.

Recent advances in high-throughput single cell sequencing have opened up new avenues into the investigation of B cell receptor (BCR) repertoires. In this study, PBMCs were collected from 17 human participants vaccinated with the split-inactivated influenza virus vaccine during the 2016-2017 influenza season. A combination of Immune Repertoire Capture (IRCTM) technology and IgG sequencing was performed on ~7,800 plasmablast (PB) cells and preferential IgG heavy-light chain pairings were investigated. In some participants, a single expanded clonotype accounted for ~22% of their PB BCR repertoire. Approximately 60% (10/17) of participants experienced convergent evolution, possessing public PBs that were elicited independently in multiple participants. Binding profiles of one private and three public PBs confirmed they were all subtype-specific, cross-reactive hemagglutinin (HA) head-directed antibodies. Collectively, this high-resolution antibody repertoire analysis demonstrated the impact evolution can have on BCRs in response to influenza virus vaccination, which can guide future universal influenza prophylactic approaches.

Iron-catalyzed aminohydroxylation of olefins.

We have discovered that N-sulfonyl oxaziridines react with a broad range of olefins in the presence of iron salts to afford 1,3-oxazolidines. This process provides access to 1,2-aminoalcohols with the opposite sense of regioselectivity produced from the copper-catalyzed oxyamination previously reported by our laboratories. Thus, either regioisomeric form of 1,2-aminoalcohols can easily be obtained from the reaction of oxaziridines with olefins, and the sense of regioselectivity can be controlled by the appropriate choice of inexpensive, nontoxic, first-row transition-metal catalyst.

Synthesis and structural characterization of molecular Dy(III) and Er(III) tetra-carbonates.

Single crystal structures of lanthanide carbonate and hydroxy-carbonate compounds have been previously reported in the literature, with the majority of these compounds being extended one- to three-dimensional compounds. Very few lanthanide compounds have been isolated that contain molecular moieties, and none have been reported for either erbium or dysprosium. Single crystals of the tetra-carbonate complexes, [C(NH(2))(3)](5)[Er(CO(3))(4)].11H(2)O (I) and [C(NH(2))(3)](4)[Dy(CO(3))(4)(H(2)O)](H(3)O).13H(2)O (II), were isolated from concentrated guanidinium carbonate solutions and characterized by single crystal X-ray diffraction studies. Compounds I and II are the first reported molecular carbonate structures for Er and Dy to be characterized via single crystal X-ray diffraction studies. Crystallographic data for I: monoclinic, space group P21/n, a = 8.8160(6) A, b = 21.0121(14) A, c = 19.6496(14) A, Z = 4. Data for II: tetragonal, space group P4/n, a = b = 15.3199(11) A, c = 7.5129(11) A, Z = 2.

The aunt and uncle effect revisited--the effect of biased parentage assignment on fitness estimation in a supplemented salmon population.

We investigated differences in the statistical power to assign parentage between an artificially propagated and wild salmon population. The propagated fish were derived from the wild population and are used to supplement its abundance. Levels of genetic variation were similar between the propagated and wild groups at 11 microsatellite loci, and exclusion probabilities were >0.999999 for both groups. The ability to unambiguously identify a pair of parents for each sampled progeny was much lower than expected, however. Simulations demonstrated that the proportion of cases in which the most likely pair of parents were the true parents was lower for propagated parents than for wild parents. There was a clear relationship between parentage assignment ability and the estimated effective number of grandparents of the progeny to be assigned. If a stringent threshold for parentage assignment was used, estimates of relative fitness were biased downward for the propagated fish. The bias appeared to be largely eliminated by either fractionally assigning progeny among parents in proportion to their likelihood of parentage or by assigning progeny to the most likely set of parents without using a statistical threshold.

N-Nosyl Oxaziridines as Terminal Oxidants in Copper(II)-Catalyzed Olefin Oxyaminations.

We report that N-4-nosyl-3-phenyloxaziridine is an effective terminal oxidant for copper(II)-catalyzed oxyamination recently developed in our labs. This oxaziridine can be prepared on multi-gram scale and is easily purified by recrystallization. The products of oxyamination using this oxaziridine bear protecting groups that can be readily removed in high yields under mild conditions.

Oxaziridine-mediated enantioselective aminohydroxylation of styrenes catalyzed by copper(II) bis(oxazoline) complexes.

We report an oxaziridine-mediated enantioselective aminohydroxylation of olefins catalyzed by a chiral copper(II) bis(oxazoline) complex. A variety of styrenic olefins undergo efficient aminohydroxylation with excellent regioselectivity and synthetically useful levels of enantioselectivty (up to 84% ee). The reaction can be conducted on multi-gram scale with as little as 2 mol% of the copper(II) catalyst. Hydrolysis of the resulting 1,3-oxazolines under acidic conditions produces N-sulfonyl amino alcohols that can be purified by recrystallization to afford very high levels of enantioselectivity.

Dietary intake of people with dementia on acute hospital wards.

The aim of this service evaluation was to understand the factors affecting meal provision on a dementia ward and assess whether meals-based dietary intake met estimated mean energy requirement and reference nutrient intake (RNI). A mixed-methods approach was adopted: 1. Mapping the dietary intake for a cohort ( n =6) of inpatients with advanced dementia over a period of four consecutive days. 2. Semi-structured interviews to explore the experiences of the professionals ( n =5) involved. Two of the participants' four-day mean intakes did not meet their estimated energy requirement based on meal provision. All participants apart from one met the target of 0.75g of protein per kg body weight per day for the general population. Several of the nutrients consumed were at or exceeded the RNI for adults of this age, although participants' mean dietary vitamin D intake was substantially below the RNI for the general population. The themes included communication, time pressure and the continuity of service provision. The meals provided were nutritionally sound. Individuals' nutritional status was improved through staff supporting them with eating. The contribution of drinks and snacks to nutrient intake warrants further exploration. Effective communication between food providers and ward areas is important. Mealtimes should reflect patient need - for example, having the main meal in the evening and a lighter option at lunch. This does not clash with the benefits of a flexible breakfast time.

Characterization of a chromosomal rearrangement responsible for producing "apparent" XY-female fall-run Chinook salmon in California.

Fluorescence in situ hybridization (FISH) was used to identify the X and Y chromosomes of offspring produced by normal and "apparent" XY-female fall-run Chinook salmon (Oncorhynchus tshawytscha) from California. FISH experiments were performed using probes to 2 sex-linked loci, growth hormone pseudogene (GH-Psi), and OtY1, as well as a probe to a sex-linked microsatellite (Omy7INRA). Comparison of FISH staining patterns between the offspring produced by normal and apparent XY-females revealed that the apparent XY-female examined transmitted a "Y-like" chromosome with an attenuated OtY1 and GH-Psi signal to half of its offspring. Segregation analysis of microsatellites derived from rainbow trout (Oncorhynchus mykiss) with respect to phenotypic sex was carried out for 2 normal and 2 apparent XY-female Chinook salmon families. Inheritance patterns of Omy7INRA were consistent with this locus being closely linked to GH-Psi in males and in apparent XY-females carrying the Y-like chromosome. Another microsatellite locus (Omm1077) was closely linked to the primary sex-determining locus (SEX) in males but not to GH-Psi/OtY1 in apparent XY-females. The FISH analyses suggest that apparent XY-female fall-run Chinook salmon in California are not the product of a Y chromosome to autosome translocation. Despite the combined FISH and inheritance analyses, we were unable to differentiate between 2 alternative explanations for apparent XY-females, namely, recombination of markers between the sex chromosomes, or a Y chromosome with a dysfunctional or missing sex-determining region.

Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1.

Spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody-drug conjugates and other targeted delivery approaches. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access. Using uniquely enabling direct complex fragment coupling crotyl- and alkallylsilylation reactions, we report a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is characterized by GI50 values in the low picomolar range, and a proof-of-concept result that the C(15) acetate may be replaced with linker functional group-bearing esters with only minimal reductions in potency.

Direct, Mild, and General n-Bu4NBr-Catalyzed Aldehyde Allylsilylation with Allyl Chlorides.

A direct, mild, and general method for the enantioselective allylsilylation of aldehydes with allyl chlorides is reported. The reactions are effectively catalyzed by 5 mol % of n-Bu4NBr, and this rate acceleration allows the use of complex allyl donors in fragment-coupling reactions and of electron-deficient allyl donors. The results are (1) significant progress toward a "universal" asymmetric aldehyde allylation reaction that can reliably and highly stereoselectively couple any allyl chloride_aldehyde combination and (2) the discovery of a novel mode of nucleophilic catalysis for aldehyde allylsilylation reactions.

A comparison of the nutrient intake of a community-dwelling first-episode psychosis cohort, aged 19-64 years, with data from the UK population.

Psychosis increases the risk of CVD, obesity and type 2 diabetes and reduces life expectancy. There are limited data comparing the dietary habits of community-dwelling first-episode psychosis sufferers - with autonomy over diet - and the general population. The data represent the retrospective evaluation of nutritional data collected between 2007 and 2013 from 143 individuals from the UK population receiving treatment for first-episode psychosis. Differences in mean nutrient intakes between the study cohort and the national sample were tested for statistical significance using independent t tests, incorporating Satterthwaite's correction where required. Mean total energy intake was lower for males (P = 0·049) and higher for females (P = 0·016) in the cohort than in the corresponding subgroups of the national sample. Females in the study cohort consumed 12·9 (95 % CI 4·3, 21·5) g more total fat per d, whilst males consumed 7·7 (95 % CI 0·5, 14·9) g less protein per d than the national sample. Males in the study also showed significantly lower mean intakes than nationally of folate, Fe, Se, vitamin D and Zn, but not vitamin C. The proportion of individuals not meeting the lower reference nutrient intakes, particularly for Se (males 54·0 % and females 57·1 %) and for Fe amongst females (29·6 %), is cause for concern regarding potentially severe deficiencies. Further exploration of dietary habits within first-episode psychosis is warranted to assess whether individuals make beneficial dietary changes for their physical and mental health and wellbeing following dietary change intervention. It would also be pertinent to assess any correlation between diet and mental health symptomology.